Down-regulation of Lon protease 1 lysine crotonylation aggravates mitochondrial dysfunction in polycystic ovary syndrome

Yuan Xie; Shuwen Chen; Zaixin Guo; Ying Tian; Xinyu Hong; Penghui Feng; Qiu Xie; Qi Yu

doi:10.1002/mco2.396

Down-regulation of Lon protease 1 lysine crotonylation aggravates mitochondrial dysfunction in polycystic ovary syndrome

MedComm (2020). 2023 Oct 9;4(5):e396. doi: 10.1002/mco2.396. eCollection 2023 Oct.

Authors

Yuan Xie¹, Shuwen Chen¹, Zaixin Guo¹, Ying Tian¹, Xinyu Hong¹, Penghui Feng¹, Qiu Xie², Qi Yu¹

Affiliations

¹ Department of Obstetrics and Gynecology National Clinical Research Center for Obstetric & Gynecologic Diseases State Key Laboratory for Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences & Peking Union Medical College Peking Union Medical College Hospital (Dongdan Campus) Beijing China.
² Department of Medical Research Center State Key Laboratory for Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Science and Peking Union Medical College Beijing China.

Abstract

Polycystic ovary syndrome (PCOS) is a prevalent reproductive endocrine disorder, with metabolic abnormalities and ovulation disorders. The post-translational modifications (PTMs) are functionally relevant and strengthen the link between metabolism and cellular functions. Lysine crotonylation is a newly identified PTM, the function of which in PCOS has not yet been reported. To explore the molecular mechanisms of crotonylation involved in the abnormalities of metabolic homeostasis and oocyte maturation in PCOS, by using liquid chromatography-tandem mass spectrometry analysis, we constructed a comprehensive map of crotonylation modifications in ovarian tissue of PCOS-like mouse model established by dehydroepiandrosterone induction. The crotonylation levels of proteins involved in metabolic processes were significantly decreased in PCOS ovaries compared to control samples. Further investigation showed that decrotonylation of Lon protease 1 (LONP1) at lysine 390 was associated with mitochondrial dysfunction in PCOS. Moreover, LONP1 crotonylation levels in PCOS were correlated with ovarian tissue oxidative stress levels, androgen levels, and oocyte development. Consistently, down-regulation of LONP1 and LONP1 crotonylation levels were also observed in the blood samples of PCOS patients. Collectively, our study revealed a mechanism by which the decrotonylation of LONP1 may attenuate its activity and alter follicular microenvironment to affect oocyte maturation in PCOS.

Keywords: LONP1; lysine crotonylation; mitochondrial dysfunction; polycystic ovary syndrome.